ES2351366T3 - 1H-FURO COMPOUNDS [3,2-C] PIRAZOL USEFUL AS QUINASE INHIBITORS. - Google Patents

Abstract

Furo[3,2-c]pyrazole derivatives of formula (I) as defined in the description, and pharmaceutically acceptable salts thereof, wherein A is an aryl or heteroaryl ring, —NHZR5 is at the ortho position to the CONH linker; —R1 and R2 are the same or different and, independently from each other, represent a hydrogen atom, or an organic residue; R3 is a hydrogen or halogen atom or an organic group; R4 is a hydrogen or halogen atom or an organic group; Z is direct bond, >C═O, or —C(═O)NH—; —R5 is hydrogen or an optionally substituted organic group or isomers, tautomers, carriers, metabolites, prodrugs, and pharmaceutically acceptable salts thereof. A process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, in particular Aurora kinases activity or IGF-1R activity, like cancer.

Description

Field of the Invention

The present invention relates to the use of furo-pyrazole derivatives, to a process for their preparation, to pharmaceutical compositions comprising them, and to their use as therapeutic agents, in particular in the treatment of disorders.

of cancer and cell proliferation.

Background Description

Malfunction of protein kinases (PK) is the marker of numerous diseases. A large part of the oncogenes and protooncogenes 10 involved in human cancers code for PK. Increased PK activities are also implicated in many non-malignant diseases, such as benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and stenosis and restenosis.

15 postoperative. PKs are also involved in inflammatory conditions and in the multiplication of viruses and parasites. PKs can play an important role in the pathogenesis of and the development of neurodegenerative disorders.

For a general reference for the malfunction or deregulation of PK 20 see, for example, Current Opinion in Chemical Biology 1999, 3, 459-465. Among the various protein kinases known in the art involved in the growth of cancer cells are the Aurora kinases, in particular Aurora

2. It was found that Aurora-2 was overexpressed in numerous tumor types

25 different Its gene locus maps to 20q13, a chromosomal region frequently amplified in many cancers, which includes breast [Cancer Res. 1999, 59 (9), 2041-4] and colon. 20q13 amplification correlates with poor prognosis in breast cancer patients with negative nodes and increased expression of Aurora-2

30 is an indicator of poor prognosis and decreased survival in patients with bladder cancer [J. Natl Cancer Inst., 2002, 94 (17), 1320-9]. For a general reference to the role Aurora-2 in the function of abnormal centrosome in cancer, see also Molecular Cancer Therapeutics, 2003, 2, 589-595.

The insulin-like growth factor receptor 1 (IGF-1R, IGF1R) is a member of the RTK insulin receptor subfamily.

There are several lines of evidence that suggest that IGF-1R signaling may contribute to tumor genesis, and that interfering with IGF-1R function represents a valid therapeutic option for cancer. Forced expression of the receptor leads to transformed growth dependent on the fibroblast ligand

5 murine and rat (for example, Kaleko M., Rutter WJ and Miller AD Mol Cell Biol vol. 10, pages 464-73, 1990; Rubini M., Hongo A., D'Ambrosio C. and Baserga R. Exp Cell Res vol. 230, pages 284-92, 1997), and such transformed cells are capable of forming tumors in vivo, with in vitro transformation and in vivo tumor formation that are dependent on the active kinase domain (reviewed in Blakesley VA, Stannard

10 B.S., Kalebic T., Helman L.J., and LeRoith D. J Endocrinol vol. 152, pages 339-44, 1997). SUMMARY OF THE INVENTION

It is an object of the invention to provide compounds, which are useful in therapy as agents against a host of diseases caused by and / or associated with a deregulated protein kinase activity and, more particularly, the activity of Aurora kinases or activity of IGF-1R. Another object is to provide compounds, which are endowed with the protein kinase inhibition activity and more particularly, Aurora kinase or IGF-1R inhibitory activity. The present invention in particular relates to new furo-pyrazole compounds and their derivatives, endowed with very high Aurora-2 kinase inhibitory activity. More specifically, the compounds of the present invention are useful in the treatment of a variety of cancers that include, but are not limited to: carcinoma such as bladder, breast, colon, kidney, liver, lung, which includes small cell lung cancer, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, 25 including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hair cell lymphoma and Burkett lymphoma; hematopoietic tumors of myeloid lineage, which include acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, which include astrocytoma, neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosa, keratoxanthoma, thyroid follicular cancer and sarcoma of

35 Kaposi

Due to the key role of PK and Aurora kinases in regulating cell proliferation, these furo-pyrazole derivatives are also useful in the treatment of a variety of cell proliferative disorders such as, for example, benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and stenosis and post-surgical restenosis.

Accordingly, in a first embodiment, the present invention provides a compound of formula (I)

image 1

10

in which -A is an aryl or heteroaryl ring, -NHZR5 is in ortho position to the CONH linker; -R1 and R2 are the same or different and, independently of each other,

15 represent a hydrogen atom, a linear or branched C1-C3 alkyl or a CONH2 group, -CH2OR ’or

CH2NR'R "or, taken together with the carbon atom to which they are attached, R1 and R2 can form a C3-C6 alkyl cycle group; R 'and R" are the same or different and, independently of each other, represent a hydrogen atom or an alkyl group

C1-C3 linear or branched or, taken together with the nitrogen atom to which they are attached, R ’and R" can form a heterocyclic ring of formula

image 1

wherein R "'is a hydrogen atom or a linear or branched C1-C3 alkyl group; -R3 is a hydrogen or halogen atom or a group selected from hydroxy, cyano, linear or branched C1-C3 alkyl, alkylamino C1-C6 and C1-C3 alkoxy;

-R4 is a hydrogen or halogen atom or a group selected from hydroxy, linear or branched C1-C3 alkyl, C1-C3 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, azetidin-1-yl, pyrrolidin-1-yl , piperidin-1-yl, (1-methyl-piperazin-4-yl), (morpholino-4-yl), (azetidin-1-yl) methyl, (pyrrolidin-1-yl) methyl, (piperidin-1- il) methyl, (1-methyl-piperazin-4

10-yl) methyl, (morpholino-4-yl) methyl, (1-methyl-piperidin-4-yloxy) methyl, (C1-alkylamino

C6) methyl and (C1-C6 dialkylamino) methyl; -Z is a direct link,> C = O, or -C (= O) NH-; -R5 is hydrogen or an optionally substituted group selected from alkyl

C1-C6, C1-C6 alkenyl, C3-C6 cycloalkyl, aryl, heteroaryl and saturated heteroaryl; 15 or its isomers, tautomers and pharmaceutically acceptable salts.

Typical cancer-specific ones that can be treated include carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma

20 pigment, keratoxanthoma, follicular thyroid cancer, and Kaposi's sarcoma.

The present invention also includes methods of synthesizing the furo-pyrazole compounds of formula (I) and pharmaceutically acceptable salts, as well as the pharmaceutical compositions comprising them.

A more complete assessment of the invention and many of its concomitant advantages will be readily obtained as it is better understood with reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Several heterocyclic compounds are known in the art as protein kinase inhibitors.

By way of example, derivatives 2-carboxamido-pyrazole and 2-ureido-pyrazole have been described as protein kinase inhibitors in international patent applications WO 01/12189, WO 01/12188, WO 02/48114 and WO 02 / 70515, all on behalf of the Pharmacia Italia SpA.

Fused bicyclic or tricyclic compounds comprising pyrazole moieties and possess kinase inhibitory activity have also been described in WO 00/69846, WO 02/12242, WO 03/028720, WO 03/097610, WO 04/007504, WO

5 04/013146, US 20050026984, WO 2005095387, US 2005215612, US 2006160874, WO 2003097609, WO 2007/009 898 and WO 2005/074 922.

The compounds of formula (I) of the invention have asymmetric carbon atoms and consequently can exist as individual optical isomers, as racemic mixtures or as any other mixture comprising a majority

10 of one of the two optical isomers, which are included in the scope of the present invention. As such, unless otherwise provided, when only one of the following tautomeric forms of formula (Ia) or (Ib) is indicated, the remainder is also considered to be within the scope of the invention:

image2

In the present description, unless otherwise specified, the term aryl group includes any aromatic carbocyclic ring system of 1 or 2 ring moieties, fused or linked to each other through a single bond, for example that includes groups phenyl, � or �-naphthyl or biphenyl.

The term "heteroaryl" includes any aromatic heterocyclic ring which may comprise a 5- or 6-membered heterocycle optionally benzocondensed with 1 to 3 heteroatoms selected from N, O or S. Non-limiting examples of heteroaryl groups according to the invention accordingly they can include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,

Indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolinyl, benzoimidazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl -1,2,3-triazolyl, and the like.

The term saturated heteroaryl includes any saturated or partially unsaturated heteroaryl as defined above. Non-limiting examples of 5-7 membered heterocycles, optionally benzo-condensed or additionally substituted, are 1,3-dioxolane, pyran, pyrrolidine, pyrroline, imidazolidine, pyrazolidine,

5 pyrazoline, piperidine, piperazine, morpholine, tetrahydrofuran, azabiciclononano and the like.

The term C1-C3 alkyl or linear or branched C1-C3 alkoxy includes any of the groups such as methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy and isopropoxy.

10 The term halogen atom includes a fluorine, chlorine, bromine or iodine atom. The term C3-C6 cycloalkyl includes any group such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Obviously, as these same cycloalkyl groups can be formed when R1 and R2 are taken together with the carbon to which they are attached, accordingly

15 Spirocyclic compounds can be obtained. As an example only, when R1 and R2 together form a cyclopentyl group, derivatives having the following general formula are considered herein:

image 1

When considering derivatives of formula (I) in which R1 or R2

20 represents a group -CH2NR’R "and R" and R "are linked together with the nitrogen atom to which they are attached, the heterocyclic moieties can be formed in this way as per the general formula. As an example, when considering R1 as hydrogen and R2 as a group -CH2NR’R "with R" and R "linked together to form a pyrrolidinyl-1-yl group, compounds having the following general formula are

25 hereby consider: When considering derivatives of formula (I) in which R1 or R2 represents a group -CH2NR'R "and R 'and R" are linked together with the nitrogen atom to which they are attached , heterocyclic moieties can be formed from this

as per the general formula. As an example, when considering R1 as hydrogen and R2 as a group -CH2NR'R "with R 'and R" linked together to form a pyrrolidinyl-1-yl group, the compounds having the following general formula are considered in the Present:

image 1

5

The inventors have surprisingly found a new class of compounds of formula (I) as defined above provided with high protein kinase inhibition activity, which have as characteristic feature an aryl or heteroaryl ring in which the substituent -NHZR5 is in ortho position to the CONH linker.

In accordance with the meanings provided for the substituents, any of the above aryl or heteroaryl groups may optionally also be substituted in one of their free positions with one or more groups, for example 1 to 6 groups, selected from: halogen, nitro, oxo (= O), carboxy, cyano, alkyl, polyfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups; aryl, heterocyclyl,

Alkyl-heterocyclyl, heterocyclyl-alkyl, amino groups and their derivatives such as, for example, alkylamino, dialkylamino, arylamino, diarylamino, ureido, alkylureido or arylureido; carbonylamino groups and their derivatives such as, for example, formylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino; hydroxy groups and their derivatives such as, for example, alkoxy, polyfluorinated alkoxy,

Aryloxy, heterocyloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy or alkylidenaminoxy; carbonyl groups and their derivatives such as, for example, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl; sulfur derivatives such as, for example, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl,

Arylsulfinyl, arylsulfonyloxy, aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl. In turn, when appropriate, each of the above substituents shall

You can substitute additionally with one or more of the groups mentioned above. The term "alkyl or alkoxy group" includes, unless otherwise provided, any linear or branched C1-C6 alkyl or alkoxy group, which

Both comprises the aforementioned C1-C3 alkyl or alkoxy groups and also comprises n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-butoxy, iso-butoxy, sec-butoxy , tert-butoxy, n-pentyloxy, n-hexyloxy, and the like.

The term "alkenyl or alkynyl group" includes, unless otherwise provided, any linear C2-C6 alkenyl or alkynyl group or

Unsaturated branched such as, for example, vinyl, allyl, 1-propenyl, isopropenyl, 1-, 2-or 3-butenyl, pentenyl, hexenyl, ethynyl, 1-or 2-propynyl, butynyl, pentinyl, hexinyl, and the like . Any linear or branched C 1 -C 6 alkyl or alkoxy group is defined by the term "alkyl or polyfluorinated alkoxy" as defined above, in which more than one

The hydrogen atom is replaced with fluorine atoms such as, for example, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethyl, 2,2,2-trifluoroethoxy, 1,2-difluoroethyl, 1,1,1,3, 3,3-hexafluoropropyl-2-yl, and the like.

The term heterocycle, heterocyclyl or heterocyclic group also includes an optionally benzo-condensed 4 to 7-membered heterocycle, which therefore encompasses aromatic heterocyclic groups also known as heteroaryl, saturated or partially unsaturated groups, with 1 to 3 heteroatoms selected from N , O and S. Examples of these 4- to 7-membered heterocyclic groups are, for example, 1,3-dioxolane, pyran, pyrrolidine; pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine,

Tetrahydrofuran, hexamethyleneimine, 1,4-hexahydrodiazepine, azetidine, and the like. The term "cycloalkenyl" includes any of the C3-C6 cycloalkyl groups which further comprise a double bond such as, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 1-cyclohexene-1-yl, 2- cyclohexen-1-yl, 3-cyclohexen-1-yl, and the like. Of all the above, it is evident to those skilled in the art that

Any group whose name has been identified as a compound name such as, for example, alkylamino, dialkylamino, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, alkylthio, aryloxy, arylalkyl, alkylcarbonyloxy and the like, should be considered to be conventionally formed from the parts of which drift So far, as an example, the term "alkoxy-heterocyclyl-alkyl" means a group

Linear or branched alkyl substituted with a heterocycle additionally substituted with

alkoxy, in which alkyl, heterocycle and alkoxy are as defined above. Also, the term "alkyl-heterocyclyloxy" means a heterocyclyloxy group further substituted with alkyl.

The term "pharmaceutically acceptable salts" encompasses commonly salts.

5 used to form alkali metal salts and to form free acid addition salts or free bases. The nature of the salt is not critical, provided it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention can be prepared from an inorganic or organic acid. Examples of such acids

10 inorganic are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from classes of aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic organic acids, the examples of which are formic, acetic, trifluoroacetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric acids, citrus, ascorbic,

15 glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesyl, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethane, 2-hydroxyethane, 2-hydroxyethane cyclohexylaminosulfonic, alginic, hydroxybutyric, galactharic and galacturonic. Base addition salts

Suitable pharmaceutically acceptable compounds of the present invention include metal salts obtained from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts obtained from N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl glucamine) and procaine. All these salts can be prepared by conventional means from the compounds

25 of the present invention, for example by reacting them with an appropriate acid or base. A preferred class of the compounds of the invention is represented by a compound of formula (I) in which A is an optionally substituted thienyl, furyl, pyrrolyl or phenyl group.

More preferably, A is a phenyl group and R4 is in the 4 position and represents hydrogen, halogen, methoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, (1-methyl-piperazin-4 -yl), (morpholino-4-yl), (azetidin-1-yl) methyl, (pyrrolidin-1-yl) methyl, (piperidin-1-yl) methyl, (1-methyl-piperazin-4-yl) methyl, (morpholino-4-yl) methyl, (1-methylpiperidin-4-yloxy) methyl, (C1-C6 alkylamino) methyl (C1-C6 dialkylamino) methyl.

35 Even more preferably, Z is> C = O.

In another preferred class of the compounds of formula (I), R1 and R2 are a methyl group or, taken together with the carbon atom to which they are attached, form a C3-C6 alkyl cycle group.

In another preferred class of compounds of formula (I), R 3 represents a hydrogen or halogen atom.

For a reference to any compound of formula (I) specific to the invention, optionally in the form of a pharmaceutically acceptable salt, see the following experimental section. As indicated above, a further object of the present invention is represented by a process for preparing the compounds of

Formula (I) and the pharmaceutically acceptable salts thereof, such process comprises: a) reaction of a bicyclic compound of formula (II):

image 1

wherein ALK is a C1-C4 alkyl group with any suitable protective agent of the nitrogen atom of pyrazole; B) acylation of the resulting compound of formula (III):

image 1

wherein ALK is as defined above and Q represents any suitable protective agent of pyrazole nitrogen, with a compound of formula (IV):

image 1

twenty

wherein A and R4 are as defined above and LG represents a suitable leaving group;

c) hydrolysis of the alkyl ester group and removal of the protective group Q of the resulting compound of formula (V):

image 1

in which ALK, A, R4 and Q are as defined above; d) reaction of the resulting compound of formula (VI):

image 1

wherein A and R4 are as defined above, with a compound of formula (VII)

10

image 1

wherein R1, R2 and R3 are as defined above, in the presence of any suitable condensing agent; e) reduce the nitro group of the resulting compound of formula (VIII)

image 1

fifteen

wherein A, R1, R2, R3, R4 and Q are as defined above;

f) acylation of the resulting compound of formula (IX):

image 1

wherein A, R1, R2, R3 and R4 are as defined above, with a compound of formula (X) or (XI):

5

R5-Z-LG (X)

R5-NCO (XI)

In which Z is> C = O or -C (= O) NH-, and R5 and LG are as defined above; g) selective deacylation of the resulting compound of formula (XII):

image 1

wherein A, R1, R2, R3, R4 and Q are as defined above and Z is

15> C = O or -C (= O) NH-, by selective hydrolysis of the ZR5 substituent of pyrazolic nitrogen to obtain a compound of formula (I) in which A, R1, R2, R3 and R4 are as defined above and Z is> C = O or -C (= O) NH-,

or f ’) treating a compound of formula (IX) as defined above with a carbonyl compound of formula W-CO-Y (XIII) in which W and Y are atoms of

hydrogen or an optionally substituted group selected from C1-C5 alkyl, C1-C5 cycloalkyl, aryl, heteroaryl or saturated heteroaryl, in the presence of a suitable reducing agent, to obtain a compound of formula (I) in which A, R1, R2, R3 and R4 are as defined above and Z is a direct link and, if you wish

5 or is necessary,

h) converting a compound of formula (I) as defined above into a compound of formula (I) different by known reactions, or converting a compound of formula (I) as defined above into a pharmaceutically acceptable salt or converting the salt of this in the compound of formula (I) free as

10 defined above. Alternatively, the compounds of the formula (I) herein can also be obtained by means of i) reducing the nitro group of the compound of formula (V) as defined above, and 15 j) acylating the resulting compound of formula (XIV ):

image 1

wherein A, R4, ALK and Q are as defined above, with a compound of formula (X) or (XI) as defined above to obtain a compound of formula (XV):

image 1

twenty

wherein A, R4, R5, ALK and Q are as defined above and Z is> C = O or -C (= O) NH-; or

j ') treating a compound of formula (XIV) as defined above with a carbonyl compound of formula W-CO-Y (XIII) as described above, to obtain a compound of formula (XV) in which A, R4, R5, ALK and Q are as defined above and Z is a direct link;

k) hydrolyze the alkyl ester group and remove the protective group Q from

resulting compound of formula (XV) in which Z is> C = O or -C (= O) NH- or a bond

direct;

l) reacting the resulting compound of formula (XVI)

image 1

Wherein A, R4, R5 and Z are as defined above, with a compound of formula (VII) as described above;

m) converting a compound of formula (I) as defined above into a compound of formula (I) different by known reactions or converting a compound of formula (I) as defined above into a pharmaceutically acceptable salt

15 or converting the salt thereof into the compound of formula (I) free as defined above.

It should be mentioned that a compound of formula (I), (II), (VI), (VIII), (IX), (XVI) as defined above may be in any of its tautomeric forms a or b, not only in the manner described before

image 1

twenty

In protected compounds, the suitable pyrazolic nitrogen protecting group that Q represents may be in the nitrogen atom in position 2, even if the isomer having Q in position 1 is preferred and is the only one indicated.

The above process is an analogy process, which can be performed according to the methods known in the art.

From the foregoing, it is apparent to those skilled in the art that if a compound of formula (I), prepared according to the above process, is obtained as a mixture of isomers, its separation into the individual isomers of formula

5 (I), carried out in accordance with conventional techniques, is still within the scope of the present invention.

According to step (a) of the process, the furo-pyrazole derivative of formula (II) is protected, according to well known methods, in the pyrazolic nitrogen atom. As an example, the above protection can occur with chlorocarbonate of

10 alkyl, in a suitable solvent such as tetrahydrofuran, dichloromethane, chloroform, acetonitrile, toluene or mixtures thereof, at a temperature ranging from about -5 ° C to about 35 ° C and for a time ranging from about 30 minutes to about 72 hours, in the presence of a suitable proton scrubber such as triethylamine or diisopropylethylamine.

According to step (b) of the process, the compound of formula (III) is subsequently reacted with any suitable acylating agent of formula

(IV) to produce the compound of formula (V), per action according to methods well known in the art for the preparation of carboxamide derivatives. Normally, within the compound of formula (IV), LG represents an atom of

20 halogen and, even more preferably, a bromine or chlorine atom. The reaction is carried out in a suitable solvent such as, for example, tetrahydrofuran, dimethylformamide, dichloromethane, chloroform, acetonitrile, toluene or mixtures thereof, at a temperature ranging from about -10 ° C to reflux and for a time ranging from approximately 30 minutes to approximately 96

25 hours, in the presence of a suitable proton scrubber such as triethylamine, N, N-diisopropylethylamine or pyridine. From the foregoing, it is clear to the experts that the above protection in the pyrazolic nitrogen atom, of step (a), is of particular advantage since it prevents acylation with the compound of formula (IV), in stage (b), in the

30 pyrazolic nitrogen atom. According to step (c) of the process, the carboxy ester functional group of the compound of formula (V) is hydrolyzed to produce the corresponding carboxy group and at the same time, the protective group Q. is removed.

The reaction is carried out under alkaline conditions, preferably by treatment with aqueous sodium or potassium hydroxide in the presence of a suitable co-solvent such as methanol or ethanol, by operation at a temperature that varies from room temperature to reflux temperature. of the mixture and for a suitable time, for example up to 72 hours.

According to step (d) of the process, the compound of formula (VI) 5 is subsequently reacted with a suitable amino derivative of formula (VII) to produce the corresponding compound of formula (VIII).

From the foregoing, it is clear to experts that this reaction can be obtained in a variety of ways and operating conditions, which are widely known in the art for the preparation of carboxamides.

As an example, the reaction between the compounds of formula (VI) and (VII) can be carried out in the presence of a coupling agent such as, for example, 2- (1 H -benzotriazol-1-yl) tetrafluoroborate) -1,1,3,3-tetramethyluronium (TBTU), 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, N-cyclohexylcarbodiimide-N'-propyloxymethyl polystyrene or N

Cyclohexylcarbodiimide-N'-methyl polystyrene, in a suitable solvent such as, for example, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, 1,4-dioxane, acetonitrile, toluene, or N, N-dimethylformamide at a temperature varying from about -10 ° C at reflux and for a suitable time, for example from about 30 minutes to about 96 hours. This reaction leads to

20 optionally carried out in the presence of a suitable catalyst, for example 4-dimethylaminopyridine, or in the presence of an additional coupling reagent such as N-hydroxybenzotriazole. Alternatively, this same reaction can also be carried out, for example, through a mixed anhydride method, by the use of a chloroformate of

Alkyl such as ethyl chloroformate, iso-butyl, or isopropyl, in the presence of a tertiary base such as triethylamine, N, N-diisopropylethylamine or pyridine, in a suitable solvent such as, for example, toluene, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, diethyl ether, 1,4-dioxane, or N, N-dimethylformamide, at a temperature ranging from about -30 ° C to room temperature.

According to step (e) of the process, the aromatic nitro group of the compound of formula (VIII) is reduced to amino. The reaction can be carried out in a variety of operative ways and conditions, which are widely known in the art to reduce a nitro group to an amino. Preferably, this reaction is carried out in a suitable solvent such as, for example, water, tetrahydrofuran,

1,4-dioxane, N, N-dimethylformamide, ethyl acetate, or a mixture thereof, in the

presence of a suitable reducing agent, such as, for example, hydrogen and a hydrogenation catalyst, or by treatment with cyclohexene or cyclohexadiene and a hydrogenation catalyst, or by treatment with tin (II) chloride, or by treatment with In and hydrochloric acid, or by treatment with sodium hypophosphite and 5 hydrogenation catalysts at a temperature ranging from 0 ° C to reflux and for a time ranging from about 1 hour to about 96 hours. The hydrogenation catalyst is usually a metal, with maximum palladium frequency, which can be used as such or on a carbon support. According to step (f) of the process, the compound of formula (IX) is subsequently reacted with any suitable acylating agent of formula (X) or (XI) to produce compounds of formula (XII), acting in accordance with methods well known in the art for the preparation of carboxamide and ureido derivatives. Normally, within the compound of formula (X), LG represents a halogen atom, preferably a chlorine atom, or a 2,4-dinitro-phenoxy group. The reaction is carried out in a suitable solvent such as, for example, tetrahydrofuran, dimethylformamide, dichloromethane, chloroform, acetonitrile, toluene or mixtures thereof, at a temperature ranging from about -10 ° C to reflux and for a time that varies from about 30 minutes to about 96 hours. If needed, the reaction is carried out in the presence of a scrubber.

Timely protons such as triethylamine, N, N-diisopropyl-ethylamine or pyridine. According to step g) of the process, the compound of formula (XII) is subsequently deacylated in the pyrazolic nitrogen atom under basic conditions and acting in accordance with conventional techniques, for example by treatment with aqueous sodium or potassium hydroxide in the presence of a suitable co-solvent

25 such as methanol, ethanol, dimethylformamide, 1,4-dioxane, or by treatment with a tertiary amine such as triethylamine or N, N-diisopropylethylamine and by the use of an alcohol such as methanol or ethanol as the solvent.

The reaction can occur at a temperature ranging from about 18 ° C to the reflux temperature of the solvent, for a time ranging from about 30 minutes to about 72 hours. Finally, according to step f ') of the process, the reaction between a compound of formula (IX) and an aldehyde or a ketone can be carried out in a variety of ways, according to conventional methods for carrying out the reductive alkylation, to give a compound of formula (I) in which Z is a direct bond. Preferably, this reaction is carried out in a suitable solvent such as, for example,

methanol, N, N-dimethylformamide, dichloromethane, tetrahydrofuran, or a mixture thereof, in the presence of a suitable reducing agent such as, for example, sodium borohydride, tetra-alkylammonium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, tetramethylammonium triacetoxy borohydride, hydrogen and

5 a hydrogenation catalyst, and in the presence of an acid catalyst, such as, for example, acetic acid, trifluoroacetic acid, at a temperature ranging from about 0 ° C to reflux and for a time ranging from about 1 hour to about 96 hours

According to step (i) of the process, the aromatic nitro group of compound 10 of formula (V) is reduced to amino. The reaction can be carried out as described above for step e) above. According to step j) of the process, the compound of formula (XIV) is subsequently reacted with any suitable acylating agent of formula

(X) or (XI) to produce compounds of formula (XV), acting as described above for step e) above.

According to step j ') of the process, the reaction between a compound of formula (XIV) and an aldehyde or a ketone can be carried out in a variety of ways, according to conventional methods to carry the reductive alkylation, to give a compound of formula (XV) in which Z is a direct bond.

20 Preferably, this reaction is carried out as described above for step f ’) above. According to step (k) of the process, the carboxy ester function of the compound of formula (XVI) is hydrolyzed to produce the corresponding carboxy group and, at the same time, the protective group Q is removed. The reaction is carried out as follows.

25 described above for step c) above. Finally according to step (k) of the process, the compound of formula

(XVI) subsequently reacted with a suitable amino derivative of formula

(VII) to carry the corresponding compound of formula (I). From the foregoing, it is clear to the experts that this reaction can be carried out in a variety of operative ways and conditions, which are widely known in the art for the preparation of carboxamides. As an example, the reaction between the compounds of formula (XVI) and (VII) can be carried out as described above for step d) above.

All starting compounds of formula (II), (IV), (VII), (VIII), (X), (XI) and 35 (XIII) are known or can be obtained according to known methods.

For a reference to the preparation of the compounds of formula (II) see WO 2004007504, as well as the following experimental section.

PHARMACOLOGY

The compounds of formula (I) are active as protein inhibitors

5 kinase, more particularly as Aurora kinase inhibitors or IGF-R1 inhibitors and consequently useful, for example, to restrict deregulated proliferation of tumor cells.

In therapy, they can be used in the treatment of various tumors, such as those reported above, as well as in the treatment of other cell proliferative disorders such as psoriasis, smooth muscle cell proliferation.

Vascular associated with atherosclerosis and stenosis and postsurgical restenosis.

The inhibitory activity and potency of the selected compounds are determined by an assay method based on the use of SPA technology (Amersham Pharmacia Biotech).

The assay consists of the transfer of a phosphate moiety labeled with radioactivity by the kinase to a biotinylated substrate. The resulting 33P biotinylated product is allowed to bind with SPA beads coated with streptavidin (biotin capacity 130 pmol / mg), and the light emitted in a scintillation counter was measured.

20 Inhibition assay for IGF-1R kinase activity The buffers / components used in the assay were as follows. The kinase buffer (KB buffer) was composed of 50 mM HEPES, 3 mM MnCl2, 1 mM DTT, 3 microM Na3VO4, pH 7.9. The enzyme buffer (EB buffer) was composed of KB buffer containing 0.6 mg / ml of BSA (bovine serum albumin). The

25 SPA scintillation beads (Product Code Number RPNQ0007, Amersham Biosciences, Piscataway, NJ USA) were prepared as a 10 mg / ml suspension in PBS containing 32 mM EDTA, 500 microM of unlabeled ATP, and Triton X100 0.1% This preparation is referred to below as "SPA pearl suspension". On the day of the test, IGF-1R was pre-phosphorylated in order to linearize the kinetics of the

30 reaction To obtain this, the desired amount of enzyme was incubated for 30 min at 28 ° C at a concentration of 1050 nM of enzyme in EB buffer containing 100 microM of unlabeled ATP. After preincubation, and immediately before the assay, this prephosphorylated IGF-1R kinase preparation was diluted to an enzyme concentration of 60 nM by the addition of 16.5 KB buffer volumes.

35 This diluted prefosphorylated enzyme is referred to below as "enzyme mixture".

The substrate used in the assay was a biotinylated carboxy-terminal peptide of the following sequence: KKKSPGEYVNIEFGGGGGK-biotin. The peptide was obtained in batches of> 95% peptide purity from American Peptide Company, Inc. (Sunnyvale, CA, USA). The "mixture of ATP", referred to below, consisted of KB buffer that

5 contains 6 nM of 33Pg-ATP (labeled with gamma phosphate, Redivue ™ Code Number AH9968, 1000-3000Ci / mmol, Amersham Biosciences Piscataway, NJ USA), 18 microM of unlabeled ATP, and 30 microM of biotinylated substrate peptide . This solution contained these components at 3X of their final reaction concentrations. The compounds to be analyzed were prepared in 100% DMSO in concentrations

10 appropriate. These preparations were subsequently diluted 33 times using KB buffer, to obtain the compound at 3X of the desired final test concentration in KB buffer containing 3% DMSO. This 3X preparation is referred to below as the "working solution of the compound." Kinase reaction: The reactions were performed in microtiter plates

15 of 96 U-bottomed wells (such as Product # 650101, Greiner Bio-One, Kremsmuenster Austria) in a final reaction volume of 30 microliters. To each test well were added 10 microliters of "working solution of the compound" containing an appropriate dilution of the compound, followed by 10 microliters of "mixture of ATP" and 10 microliters of "enzyme mixture", thus beginning the

20 reaction. The contents of the well were immediately mixed by pipetting, and the reactions were incubated for 60 minutes at room temperature. After incubation, the reactions were stopped by the addition of 100 microliters / well of "SPA pearl suspension". The wells were incubated for an additional 15 minutes at room temperature, then 110 microliters were extracted from each well and

25 were transferred to separate wells of opaque 96-well scintillation counting plates (such as OptiPlate ™ -96, PerkinElmer LAS, Inc. Boston, MA, USA), each with 100 microliters / well of 5 M CsCl. After 4 hours of rest at room temperature to allow flotation of the SPA beads, these plates were read using a scintillation counter (Packard TopCount NXT, PerkinElmer LAS,

30 Inc. Boston, MA, USA) in order to quantify the light emitted from each well (proportional to the amount of phosphate incorporated into the substrate peptide during the kinase reaction).

Many of the steps described above, such as those involving the dilution of the compound, the addition of the mixtures to the reaction, and the transfer of the finished reaction to the counting plates can be automated using robotic pipetting stations (such as Multimek and Biomek liquid dispensers, Beckman Coulter Inc., Fullerton CA USA), and a dilution curve of a known kinase inhibitor such as staurosporine can be routinely included as a positive control for IGF-1R inhibition. Results: the data were analyzed using the 5 computer program package "Assay Explorer" (Elsevier MDL, San Leandro, CA 94577). For concentrations of the compound alone, the inhibitory activity was usually expressed as% inhibition obtained in the presence of the compound, compared to the total activity of the enzyme obtained when the inhibitor was omitted. Compounds that show the desired inhibition can be analyzed

10 additionally in order to study the potency of the inhibitor through the calculation of IC50. In this case, inhibition data obtained using serial dilutions of the inhibitor can be adjusted by nonlinear regression using the following equation:

image 1

where vb is the baseline velocity, v is the observed reaction velocity, vo is the velocity in the absence of the inhibitors, and [I] is the concentration of the inhibitor.

Western blot analysis of receptor phosphorylation after stimulation with IGF-1 in human breast cancer cells MCF-7

MCF-7 cells (ATCC # HTB-22) were seeded in culture plates of

20 12-well tissues at a rate of 2x10 ^ 5 cells / well in E-MEM medium (MEM + Earle's BSS + 2 mM glutamine + 0.1 mM non-essential amino acids) + 10% FCS, and incubated during night at 37 ° C, 5% CO2, 100% relative humidity. The cells were subsequently deprived by the replacement of E-MEM + 10% FCS with E-MEM + 0.1% BSA, and incubated overnight. After this incubation,

The wells were treated with the desired concentrations of the compound for 1 hour at 37 ° C, and subsequently stimulated with 10 nM of recombinant human IGF-1 (Invitrogen, Carlsbad, CA, USA) for 10 minutes at 37 ° C. The cells were subsequently washed with PBS and lysed in 100 microliters / well of cell lysis buffer (Mammalian Protein Extraction Reagent M-PER [Product

30 # 78501, Pierce, Rockford, IL, USA] + 10 mM EDTA protease inhibitor cocktail + [Sigma-Aldrich product # P8340] + phosphatase inhibitor cocktail [Sigma-Aldrich products # P2850 + # P5726]). The cell lysates were clarified by centrifugation at 10,000xg for 5 minutes, and 10 microg / lane lysate protein was run on NuPAGE gels (NuPAGE 4-12% 10-lane Bis-Tris gels,

Invitrogen) with MOPS run buffer, subsequently transferred to Hybond-ECL nitrocellulose filters (Amersham Biosciences, Little Chalfont, Buckinghamshire, UK) using Mini PROTEAN II cameras (Bio-Rad Laboratories, Hercules, CA, USA). Filters carrying transferred protein were incubated for 1 hour in blocking buffer (TBS + 5% BSA + 0.15% Tween 20), and probed for 2 hours in the same buffer containing 1/1000 antibody anti-phosphorus rabbit IGF1R TyR1131 / InsRTyr 1146 (product # 3021, Cell Signaling Technology, Beverly, MA, USA) for the detection of phosphorylated IGF-1R, or 1/1000 dilution of IGF-Ir antibody (H-60) rabbit (product # sc-9038, Santa Cruz Biotechnology, 10 Inc., Santa Cruz, CA, USA) for the detection of the total IGF-1R chain. In each case, the filters were subsequently washed for 30 minutes with several changes of TBS + 0.15% Tween 20, and incubated for 1 hour in wash buffer containing 1/5000 dilution of peroxidase-conjugated anti-rabbit IgG of radish (Amersham, product # NA934), then washed again and

15 developed using the ECL chemiluminescent system (Amersham) according to the manufacturer's recommendations. Unless otherwise indicated, the reagents used were Sigma-Aldrich, St. Louis, MO, USA. The growth factor induced phosphorylation of the S6 ribosomal protein in primary human fibroblasts

20 S6 ribosomal protein phosphorylation in response to the stimulation of normal human dermal fibroblast growth factor (NHDF) was used to evaluate the potency of the compound to inhibit IGF-1 induced signal transduction in cells, and the selectivity towards the stimulation of EGF and PDGF. NHDF cells obtained from PromoCell (Heidelberg, Germany), were maintained

25 to 37 ° C in a humidified atmosphere with 5% CO2 in Complete Fibroblast Growth Medium (PromoCell). In the assay, NHDF were seeded in 384-well tissue culture plates (black transparent and flat bottom plates; Matrix Technologies Inc., Hudson, NH, USA) at a density of 5000 cells / well in serum-free medium that contains 0.1% bovine serum albumin (BSA) and incubated

30 for 5 days. The deprived cells were treated for 1 hour with desired doses of compounds and subsequently stimulated for an additional 2 hours with 10 nM IGF-1 (Invitrogen Corp., CA, USA), 10 nM EGF (Gibco BRL, USA) or 1 nM of PDGF-B / B (Roche Diagnostics GmbH, Germany). The cells were subsequently fixed in PBS / 3.7% paraformaldehyde for 20 minutes at room temperature,

35 were washed X2 with PBS, and permeabilized with PBS / 0.3% Triton X-100 for 15

minutes The wells were subsequently saturated with PBS / 1% skim milk powder (Bio-Rad Laboratories, Hercules, CA, USA) for 1 hour, and subsequently probed for 1 hour at 37 ° C with anti-phospho-S6 antibody (Ser 235 / 236) (Cell Signaling Technology, Beverly, MA, USA, cat. # 2211) at a 5 1/200 dilution in PBS / 1% milk / 0.3% Tween 20. The wells were subsequently washed twice with PBS, and incubated for 1 hour at 37 ° C with PBS / 1% milk / 0.3% Tween 20 + 1 microg / ml DAPI (4,6-diamidino-2-phenylindole) + 1/500 secondary antibody Cy5 ™ anti-goat rabbit conjugate (Amersham Biosciences, Little Chalfont, Buckinghamshire, UK). The wells were subsequently washed X2 with PBS, and 10 40 microliters of PBS were left in each well for immunofluorescence analysis. Fluorescence images on the DAPI and Cy5 ™ channels were obtained, stored and analyzed automatically using a Cellomics ArrayScan ™ IV instrument (Cellomics, Pittsburgh, USA); Cellomics Cytotoxicity Algorithm was used to quantify phospho-associated cytoplasmic fluorescence

15 S6 (Cy5 ™ signal parameter: "Smooth Mass-pH mean") for each cell in 10 fields / well, and finally expressed as a mean population value. Unless otherwise indicated, reagents were obtained from Sigma-Aldrich, St. Louis, MO, USA. Aurora-2 activity inhibition assay

20 Kinase reaction: 8 µM biotinylated peptide (4 repeats of LRRWSLG), 10 µM ATP (0.5 uCi of P33-ATP), 7.5 ng Aurora 2, inhibitor in a final volume of 30 µl buffer (50 mM HEPES, pH 7.0, 10 mM MgCl2, 1 mM DTT, 0.2 mg / ml BSA, 3 µM orthovanadate) were added to each well of a 96-well U-bottom plate . After 60 minutes incubation at

At room temperature, the reaction was stopped and the biotinylated peptide was captured by the addition of 100 µl of pearl suspension. Stratification: 100 µl of 5 M CsCl was added to each well and allowed to park 4 hours before counting the radioactivity in the Top-Count instrument. Determination of IC50: inhibitors were analyzed at different

30 concentrations ranging from 0.0015 to 10 µM. The experimental data was analyzed with the GraphPad Prizm computer program using the four-parameter logical equation:

image 1

where x is the logarithm of the inhibitor concentration, and is the answer: y 35 starts at the bottom and goes to the top with a sigmoid shape.

Ki calculation:

Experimental method: The reaction was carried out in buffer (10 mM Tris, pH 7.5, 10 mM MgCl2, 0.2 mg / ml BSA, 7.5 mM DTT) containing 3.7 nM of enzyme, histone and ATP (constant ratio of cold ATP / marked 1/3000). The reaction

5 was stopped with EDTA and the substrate was captured on a phosphomembrane (Millipore Multiscreen 96-well plates). After intensive washing, the multiscreen plates were read in a Top Counter. The control (zero time) for each concentration of ATP and histone was measured. Experimental design: Reaction rates are measured at four

10 concentrations of ATP, substrate (histone) and inhibitor. A concentration matrix of 80 points was designed around the respective Km values of ATP and substrate and the IC50 values of the inhibitor (0.3, 1, 3, 9 times the Km or the IC50 values). A preliminary time course experiment in the absence of the inhibitor and at the different concentrations of ATP and substrate allows the selection of a single time

15 end point (10 min) in the linear range of the reaction for the Ki determination experiment. Kinetic parameter estimates: The kinetic parameters were estimated by simultaneous nonlinear minimum square regression using [Ec.1] (competitive inhibitor with respect to ATP, random mechanism) using the data set

20 full (80 points):

image3

where A = [ATP], B = [Substrate], I = [inhibitor], Vm = maximum speed, the dissociation constants Ka, Kb, Ki of the ATP, substrate and inhibitor respectively, cooperative factor � and � between the union of the substrate and ATP and the substrate binding e

25 inhibitor respectively. The compounds of the invention were further analyzed, in vitro, to evaluate the antiproliferative effect in cell cultures. In vitro cell proliferation assay The human colon cancer cell line HCT-116 was seeded at the rate of

30 5000 cells / cm2 in 24-well plates (Costar) using F12 medium (Gibco) supplemented with 10% FCS (EuroClone, Italy) 2 mM L-glutamine and 1% penicillin / streptomycin and maintained at 37 ° C, 5 % CO2 and 96% relative humidity. The next day, the plates were treated in duplicate with 5 ul of an appropriate dilution from a 10 mM standard in DMSO. Two wells of untreated controls were included in each plate. After 72 hours of treatment, the medium was removed and the cells were detached from each well using 0.5 ml of 0.05% (w / v) trypsin, 0.02% (w / v) EDTA (Gibco ). The samples were diluted with 9.5 ml of Isoton (Coulter) and counted using a Multisizer 3 cell counter (Beckman Coulter). Data were evaluated as percent of control wells:

image 1

The IC50 values were calculated by the LSW / Data Analysis using the 10 Microsoft Excel sigmoid curve fit.

Given the above tests, the compounds of formula (I) of the invention resulted in a marked kinase inhibitory activity, for example Aurora-2 inhibitory activity. See, as an example, the following table I that reports the experimental data of some representative compounds

15 of the invention analyzed as Aurora-2 kinase inhibitors (IC50 nM) and for its cellular antiproliferative effect (IC50 nM).

Table 1

Compound (1) [Formula (I), R1 = R2 = methyl, R3 = R4 = H, Z = CO; R5 = pyrrol-2-yl]: 3-2 - [(1 H -pyrrol-2-carbonyl) amino] benzolamino] -1H-furo [3,2c] pyrazole-5- (1-methylphenyl-ethyl) amide carboxylic

Compound

Inhibition of Aurora-2 IC50 (nM) IC50 cell antiproliferation (nM)

(one)

6 5

It should be mentioned that the Aurora-2 inhibitory activity of compound (1) is surprisingly high. The following compounds, analyzed according to the methods described in the previous pharmacology section, all showed values of

IC50 for the inhibition of Aurora-2 less than 50 nM: 3- {2 - [(thiophene-2-carbonyl) -amino] benzoylamino} -1H-furo (1-methyl-1-phenyl-ethyl) -amide [3,2-c] pyrazol-5-carboxylic (2); 3- {2 - [(1H-Pyrrole-2-carbonyl) 5 amino] -benzoylamino} -1H-furo [3,2- (2-fluoro-phenyl) -1-methyl-ethyl] -amide -c] pyrazole-5-carboxylic acid) (5); 3- {2 - [(1-Methyl-1 H -pyrrole-2-carbonyl) -amino] benzoylamino} -1H-furo [3,2-c] (1-methyl-1-phenyl-ethyl) -amide pyrazole-5-carboxylic (7); 3- {2 - [(2-Methyl-2H-pyrazol-3-carbonyl) -amino] benzoylamino} -1H-furo [3,2-c] (1-methyl-1-phenyl-ethyl) -amide pyrazole-5-carboxylic (8); 3- {2 - [(1-Methyl-1H-pyrazol-3-carbonyl) -amino] benzoylamino} -1H-furo [3,2-c (1-methyl-1-phenyl-ethyl) -amide ] pyrazole-5-carboxylic (9); 3- (2-Benzoylamino-benzoylamino) -1Huro [3,2-c] pyrazol-5-carboxylic acid (1-methyl-1-phenyl-ethyl) -amide (10); 3- {2 - [(5-Methyl-1 H -pyrazol-3-carbonyl) -amino] 15 benzoylamino} -1H-furo [3,2-c (1-methyl-1-phenyl-ethyl) -amide ] pyrazole-5-carboxylic (11); 3- {2 - [(thiazol-4-carbonyl) -amino] benzoylamino} -1H-furo [3,2-c] pyrazol-5-carboxylic acid (1-methyl-1-phenyl-ethyl) -amide ( 12); 3- {4- (4-Methyl-piperazin-1-yl) -2 - [(1 H -pyrrol-2-carbonyl) -amino] -benzoylamino} -1H (1-methyl-1-phenyl-ethyl) -amide -furo [3,2-c] pyrazol-5-carboxylic acid (13);

3- {4- (4-Methyl-piperazin-1-yl) -2 - [(1-methyl-1H-pyrrol-2-carbonyl) -amino] 20 (1-methyl-1-phenyl-ethyl) -amide] -benzoylamino} -1H-furo [3,2-c] pyrazol-5-carboxylic acid (14) and 3- {2 - [(1-methyl-1H-imidazole) -methyl-1-phenyl-ethyl) -amide -2-carbonyl) -amino] benzoylamino} -1H-furo [3,2-c] pyrazol-5-carboxylic (15).

In addition, the compounds analyzed resulted in a very marked antiproliferative effect.

From the foregoing, the new compounds of formula (I) of the invention appear to be provided with a biological profile, taken together, which is unexpectedly superior to that of the prior art and, consequently, are particularly advantageous, in the therapy against associated proliferative disorders

30 with an altered kinase activity, in particular altered Aurora-2 kinase activity.

The compounds of the present invention can be administered as single agents or, alternatively, in combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with

35 cytostatic or cytotoxic agents, antibiotic agents, alkylating agents,

antimetabolite agents, hormonal agents, immunological agents, interferon-like agents, cyclooxygenase inhibitors (for example, COX-2 inhibitors), matrix metalloprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents , anti-HER agents,

5 anti-EGFR agents, anti-angiogenesis agents (eg, angiogenesis inhibitors), farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdk inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like.

10 If formulated as a fixed dose, such combination products employ the compounds of the present invention within the dose range described below and the other pharmaceutically active agents within the approved dose range. The compounds of formula (I) can be used sequentially with agents

15 known anticancer when a combination formulation is inappropriate. The compounds of formula (I) of the present invention, suitable for administration to a mammal, for example, to humans, can be administered by the usual routes and the dose level depends on the age, weight and conditions of the patient and route of administration.

For example, a suitable dose adopted for oral administration of a compound of formula (I) may vary from about 10 to about 500 mg per dose, from 1 to 5 times per day. The compounds of the invention can be administered in a variety of dosage forms, for example, orally, in the form of tablets, capsules, sugar or film-coated tablets, solutions

25 or liquid suspensions; rectally in the form of suppositories; parenteral, for example, intramuscularly, or through intravenous and / or intrathecal and / or intraspinal injection or infusion.

The present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt of this in association with a pharmaceutically acceptable excipient, which may be a carrier or diluent. Another object is accordingly the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for treating a disease caused by and / or associated with a protein kinase activity. deregulated, in particular to treat a disease caused by and / or associated with activity

deregulated from IGF-1R or Aurora kinases, preferably with a deregulated activity of Aurora kinase. Such medication also provides tumor angiogenesis and inhibition of metastasis.

The treated disease is preferably selected from the group consisting

5 in cancer, cell proliferative disorders, viral infections, retinopathies that include diabetic and neonatal retinopathies and age-related macular degeneration, atherosclerosis and conditions involving vascular smooth muscle proliferation or neointimal formation such as restenosis after angioplasty or surgery , vascular graft disease, as it may occur after

10 vascular or organ transplantation, acromegaly and disorders secondary to acromegaly as well as other hypertrophic conditions in which IGF / IGF-1R signaling is involved, such as benign prostatic hyperplasia, psoriasis, fibrotic lung disease, pulmonary fibrosis, pathologies related to chronic or acute oxidative stress or tissue damage induced by hyperoxia and disorders

15 metabolics in which high levels of IGF or IGF-1R activity are involved, such as obesity. Another object of the present invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament with antitumor activity.

According to the invention, the treated cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma , osteosarcoma, xeroderma pigmentosa, keratoxanthomas, follicular thyroid cancer and sarcoma of

25 Kaposi In addition, the treated cancer can be selected from the group consisting of breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer, gastric cancer, clear renal cell carcinoma, uveal melanoma, multiple myeloma, rhabdomyosarcoma , Ewing's sarcoma, Kaposi's sarcoma and medulloblastoma.

30 The treated cell proliferative disorder is selected from the group consisting of benign prostatic hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and stenosis and postsurgical restenosis. The pharmaceutical compositions containing the compounds of the

The invention is usually prepared following conventional methods and administered in a suitable pharmaceutical form.

For example, solid oral forms may contain, together with the active compound, diluents, for example, lactose, dextrose, sucrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example, silica, talc, stearic acid,

5 magnesium or calcium stearate, and / or polyethylene glycols; binding agents, for example, starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents, for example, starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; dyes; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates; Y,

10 in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations can be prepared in a known manner, for example, by mixing, granulating, tabletting, sugar coating processes or film coating.

Liquid dispersions for oral administration may be, for example, 15 syrups, emulsions and suspensions. As an example, syrups may contain, as a carrier, sucrose or sucrose with glycerin and / or mannitol and sorbitol. The suspensions and emulsions may contain, as examples of the carriers, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols, for example, propylene glycol and, if desired, an amount suitable lidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain, as a carrier, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions or they may contain propylene glycol as a carrier.

The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester or lecithin surfactant. In order to better illustrate the present invention, without imposing any limitations, the following examples are given below.

EXPERIMENTAL SECTION

The following HPLC method was used in the analysis of the compounds, as specified in the synthesis examples set forth below. As used herein, the term "Rt" refers to the retention time (minutes) for the compound using the HPLC method specified below.

LC-MS method

The HPLC / MS was performed on a Waters X Terra RP 18 column (4.6 x 50 mm,

5 3.5 mm) using a Waters 2790 HPLC system equipped with a Waters 996 PDA detector and a Micromass individual quadrupole mass spectrometer mod. ZQ, equipped with an electrospray ion source (ESI). Mobile phase A was 5 mM ammonium acetate buffer (pH 5.5 with acetic acid / acetonitrile 95: 5), and mobile phase B was water / acetonitrile (5:95). Gradient from 10 to 90% of B in 8 minutes, retention of

10 90% of B 2 min. UV detection at 220 nm and 254 nm. Flow rate 1 ml / min. Injection volume 10 l. Full scan, mass range from 100 to 800 amu. The capillary voltage was 2.5 KV; the source temperature was 120 ° C; the cone was 10 V. Retention times (LC-MS Rt) are given in minutes at 220 nm or 254 nm. The masses are given as m / z ratio.

Example 1 1-Ethyl ester 5-propyl ester of 3-amino-furo [3,2-c] pyrazol-1,5-dicarboxylic acid

image 1

A solution of ethyl chlorocarbonate (4.90 ml, 51.7 mmol) in tetrahydrofuran (THF, 60 ml) was slowly added to a mixture of 3-amino-1H-furo [3,2-c propyl ester propyl ester. ] pyrazole-5-carboxylic acid (12.0 g, 50.2 mmol) and diisopropylethylamine (DIEA, 51.5 ml, 301 mmol) in THF (300 ml), keeping the temperature in the range of -5 and -10 ° C. The reaction was maintained at the same temperature for 5

25 minutes later it was allowed to reach room temperature. The obtained mixture was evaporated to dryness in vacuo and the residue was extracted with ethyl acetate (AcOEt) and water. The organic phase was separated, dried over sodium sulfate and evaporated to dryness. The resulting crude material was triturated with diethyl ether to give 13.7 g of the title compound as a white solid.

LC-MS: Rt 4.87; [M + H] + 282. 1H NMR (400 MHz, DMSO-D6) � ppm 0.97 (t, 3 H) 1.35 (t, 3 H) 1.67 -1.81 (m, 2 H ) 4.28 (t, 2 H) 4.36 (q, 2 H) 6.35 (s, 2 H) 7.39 (s, 1 H).

Example 2

1-Ethyl ester 5-propyl ester of 3- (2-nitro-benzoylamino) -furo [3,2c] pyrazol-1,5-dicarboxylic acid

image4

To a solution of 1-ethyl ester 5-propyl ester of 3-amino-furo [3,2-c] pyrazol 1,5-dicarboxylic acid (500 mg, 1,606 mmol) and diisopropylethylamine (DIEA, 0.824 ml, 4.818 mmol) in tetrahydrofuran (THF, 20 ml) at 0 ° C, 2-nitro-benzoyl chloride was added

10 (0.318 ml, 2.409 mmol). The reaction mixture was kept at the same temperature for 10 minutes subsequently allowed to reach room temperature and allowed to react overnight. The solvent was removed in vacuo, the residue was dissolved in dichloromethane (DCM) and washed with 10% acetic acid solution (AcOH), water, saturated NaHCO3 and brine. The crude product was purified on silica gel (eluent

Dichloromethane / methanol 96/4) yielding 512 mg (69%) of the title compound. LC-MS: Rt 7.48; [M + H] + 431. 1 H NMR (400 MHz, DMSO-D6) � ppm 0.98 (t, 3 H) 1.41 (t, 3 H) 1.68 -1.82 (m, 2 H ) 4.31 (t, 2 H) 4.48 (q, 2 H) 7.54 (s, 1 H) 7.76-7.96 (m, 3 H) 8.18 (d, 1 H) 12.09 (s, 1 H). By the operation in an analogous way and by the reaction of 1-ethyl ester 5-propyl

20-3-amino-furo- [3,2-c] pyrazol-1,5-dicarboxylic acid ester with the corresponding acyl chloride derivative, thus the following compounds were prepared: 1-ethyl ester 5-propyl ester of 3- [4- (4-methyl-piperazin-1-yl) -2-nitrobenzoylamino] -furo [3,2-c] pyrazol-1,5-dicarboxylic acid LC-MS: Rt 4.65; [M + H] + 529.

25 1 H NMR (400 MHz, DMSO-D6) � ppm 0.97 (t, J = 7.38 Hz, 3 H) 1.40 (t, J = 7.07 Hz, 3 H) 1.68 -1 , 81 (m, 2 H) 2.20 -2.28 (m, 3 H) 2.42 -2.49 (m, 4 H) 3.36 -3.44 (m, 4 H) 4.31 (q, J = 6.58 Hz, 2 H) 4.48 (q, J = 7.07 Hz, 2 H) 7.24 (dd, J = 8.90, 2.44 Hz, 1 H) 7 , 45 (d, J = 2.44 Hz, 1 H) 7.51 -7.53 (m, 1 H) 7.72 (d, J = 8.78 Hz, 1 H) 11.87 (s, 1 HOUR).

Example 3 30 3- (2-Amino-benzoylamino) -furo [3,2-c] pyrazol-5-carboxylic acid

image 1

To a solution of 1-ethyl ester 5-propyl ester of 3- (2-nitro-benzoylamino) furo [3,2-c] pyrazol-1,5-dicarboxylic acid (7.6 g, 0.0176 mol) in methanol (100 ml), 2N NaOH (44.1 ml, 0.0882 mmol) was added. The mixture was refluxed gently for

5 8 hours, then the solvent was evaporated in vacuo, and the residual aqueous solution was diluted with water and ice. Hydrochloric acid (12 N) was added until pH 2. The yellowish solid that precipitated was collected, washed with water and dried under vacuum at 60 ° C. In this way 6.5 g of the title compound were obtained.

LC-MS: Rt 1.13; [M + H] + 317.

10 By the operation in an analogous manner and by the use of 1-ethyl ester 5-propyl ester of 3- [4- (4-methyl-piperazin-1-yl) -2-nitro-benzoylamino] -furo [3 , 2-c] pyrazole-1,5-carboxylic acid as starting material, the following compounds were prepared in this way: 3- [2-Amino-4- (4-methyl-piperazin-1-yl) -benzoylamino] -furo acid [3,2-c] pyrazole-5

15 carboxylic. [M + H] + 415 Example 3- (2-Nitro-benzoylamino) -1H-furo [3,2c] pyrazole-5-carboxylic acid 1 (Methyl-1-phenyl-ethyl) -amide

image5

3- (2-Amino-benzoylamino) -furo [3,2-c] pyrazol-5-carboxylic acid (11.6 g, 0.03668 mol) was dissolved in anhydrous dimethylformamide (DMF, 70 ml). Diisopropylethylamine (DIEA, 31.4 ml, 0.1834 mol), cumylamine (7.43 ml, 0.055 mol) and 2- (1H-benzotriazol-1-yl) -1,1,3,3- tetrafluoroborate were added tetramethyluronium (TBTU, 15.31 g, 0.0476 mol) respectively. The solution was stirred at room temperature overnight. It was then poured into a saturated solution of sodium bicarbonate (700 ml) and extracted with dichloromethane (2 X 250 ml). The organic phase was washed with water and dried over Na2SO4. The solution was subsequently evaporated to dryness, taken with toluene and evaporated to dryness, taken with ethyl ether and filtered. The solid was subsequently purified by flash column chromatography on silica gel 5 eluting with dichloromethane-methanol 46/4. The title compound was obtained from this

mode (3.87 g, 24.4% yield). LC-MS: Rt 5.17; [M + H] + 434; 1 H NMR (400 MHz, DMSO-D6) � ppm 1.70 (s, 6 H) 7.16-7.24 (m, 1 H) 7.27

7.34 (m, 2 H) 7.36 -7.44 (m, 3 H) 7.74 -7.82 (m, 2 H) 7.87 (ddd, 1 H) 8.15 (d, 1 H) 10 8.18 (s, 1 H) 11.29 (s, 1 H) 12.50 (s, 1 H).

By operation in an analogous manner and by the reaction of 3- (2-nitrobenzoylamino) -furo [3,2-c] pyrazol-5-carboxylic acid with the appropriate amino derivative, the following compounds were prepared in this way:

3- (2-Nitro-benzoylamino) -1H15 furo [3,2-c] pyrazol-5-carboxylic acid [1- (2-fluoro-phenyl) -1-methyl-ethyl] -amide LC-MS: Rt 5.23; [M + H] + 452;

1 H NMR (400 MHz, DMSO-D6) � ppm 1.76 (s, 6 H) 7.00 -7.21 (m, 2 H) 7.22 7.33 (m, 1 H) 7.35 - 7.45 (m, 2 H) 7.72 -7.82 (m, 2 H) 7.83 -7.92 (m, 1 H) 8.13 (d, 1 H) 8.21 (s, 1 H) 11.28 (s, 1 H) 12.50 (s, 1 H)

3- (2-Nitro-benzoylamino) -1H-furo [3,2-c] pyrazol-5-carboxylic acid ((R) -1-phenyl-ethyl) -amide; [M + H] + 420; 3- (2-Nitro acid ((S) -1-phenyl-ethyl) -amide ((S) -1-phenyl-ethyl) -amide (1-phenyl) -amide

benzoylamino) -1H-furo [3,2-c] pyrazol-5-carboxylic acid; [M + H] + 420; 3- (2-Nitro-benzoylamino) -1H-furo [3,2-c] pyrazol-5-carboxylic acid; [M + H] + 432; 3- (2-Nitro-benzoylamino) -1H (-1) phenyl-2-pyrrolidin-1-yl-ethyl) -amide

Furo [3,2-c] pyrazol-5-carboxylic; [M + H] + 489.

By the operation in an analogous way and by the reaction of 3- [2-Amino-4 (4-methyl-piperazin-1-yl) -benzoylamino] -furo [3,2-c] pyrazol-5-carboxylic acid with the appropriate amino derivative, the following compounds were prepared in this way:

3- [4- (4-Methyl-piperazin-1-yl) -230 nitro-benzoylamino] -1H-furo [3, [1- (2-fluoro-phenyl) -1-methyl-ethyl] -amide [3, 2-c] pyrazol-5-carboxylic; [M + H] + 532.

Example 5- (2-Amino-benzoylamino) -1H-furo [3,2c] pyrazol-5-carboxylic acid (1-methyl-1-phenyl-ethyl) -amide

image 1

To a solution of 3- (2-nitro-benzoylamino) 1H-furo [3,2-c] pyrazol-5-carboxylic acid (1-methyl-1-phenyl-ethyl) -amide (1 g, 0.0023 mol) in ethanol (30 ml) tin chloride dihydrate (2.08 g, 0.00923 mol) was added. The mixture was heated to reflux.

5 for 4 hours. After cooling, the solvent was evaporated to dryness and the crude product was purified by flash column chromatography on silica gel (eluting with dichloromethane-methanol 47/3. The isolated product was triturated with ethyl ether and dried under vacuum, which produces 550 mg of the title compound (59% yield).

10 LC-MS: Rt 4.34; [M + H] + 404; 1 H NMR (400 MHz, DMSO-D6) � ppm 1.69 (s, 6 H) 6.46 -6.72 (m, J = 6.95, 6.95 Hz, 3 H) 6.76 (dd , 1 H) 7.13-726 (m, 302 H) 7.27-7.35 (m, 3 H) 7.37-7.46 (m, 2 H) 7.78 (d, J = 6 , 71 Hz, 1 H) 8.31 (s, 1 H) 10.51 (s, 1 H) 12.46 (s, 1 H). Alternatively, the same product can be obtained by following the

15 procedure reported below: To a solution of 3- (2-nitro-benzoylamino) 1H-furo [3,2-c] pyrazol-5-carboxylic acid (1-methyl-1-phenyl-ethyl) -amide ( 2.6 g, 0.006 mol) in ethyl acetate (200 ml) 10% Pd / C (250 mg) was added. The mixture was hydrogenated under pressure of 50 psi of hydrogen using a Parr apparatus. The catalyst was renewed every 8 hours and the reaction

20 was carried out for a total of 40 hours. The catalyst was subsequently filtered and washed with ethyl acetate. The organic phase was evaporated in vacuo to dryness, and the solid thus obtained was triturated with ethyl ether yielding 1.49 g of the title compound.

By analogous operation the following 3- (2-Aminobenzoylamino) -furo [3,2-c] pyrazole derivatives were prepared by the corresponding derivatives of 3- (2-nitro-benzoylamino) -furo [3,2 -c] pyrazole: 3- (2-amino-benzoylamino) -1Hfuro [3,2-c] pyrazol-5-carboxylic acid LC-MS [1- (2-fluorophenyl) -1-methyl-ethyl] -amide : Rt 5.13; [M + H] + 422; 1 H NMR (400 MHz, DMSO-D6) � ppm 1.75 (s, 6 H) 6.51 -6.64 (m, 3 H) 6.78 (d, 1 H) 7.03 -7.31 (m, 4 H) 7.34 (s, 1 H) 7.40 (ddd, 1 H) 7.77 (d, 1 H) 8.34 (s, 1 H) 10.50 30 (s, 1 H) 12.46 (s, 1 H)

3- (2-Amino-benzoylamino) -1H-furo [3,2-o] pyrazol-5-carboxylic acid ((R) -1-phenylethyl) -amide; [M + H] + 390; 3- (2-Amino-benzoylamino) -1H-furo [3,2-c] pyrazol-5-carboxylic acid ((S) -1-phenylethyl) -amide; [M + H] + 390; 3- (2-Amino-benzoylamino) -1H-furo [3,2c] pyrazol-5-carboxylic acid 5 (1-phenylcyclopropyl) -amide; [M + H] + 402; 3- (2-Amino-benzoylamino) -1Huro [3,2-c] pyrazol-5-carboxylic acid ((S) -1-phenyl-2-pyrrolidin-1-yl-ethyl) -amide; [M + H] + 459. 3- [2-Amino-4- (4-methyl-piperazin-1) [1- (2-fluoro-phenyl) -1-methyl-ethyl] -amide

10-yl) -benzoylamino] -1H-furo [3,2-c] pyrazol-5-carboxylic; LC-MS: Rt 3.73; [M + H] + 502; 1 H NMR (400 MHz, DMSO-d6) � ppm 1.67 (s, 6 H) 2.20 (s, 3 H) 2.38 -2.43 (m,

4 H) 3.14 -3.21 (m, 4 H) 6.15 (d, J = 2.44 Hz, 1 H) 6.17 -6.24 (m, 1 H) 6.58 (br s., 2 H) 7.13-7.19 (m, 1 H) 7.24 -7.31 (m, 3 H) 7.35-7.40 (m, 2 H) 7.67 ( d, J = 9.02 Hz, 1 H) 15 8.27 (s, 1 H) 10.12 (s, 1 H) 12.34 (br. s., 1 H)

Example 3- (2-Methyl-1-phenyl-ethyl) -amide 3- {2 - [(1H-Pyrrol-2-carbonyl) -amino] benzoylamino} -1H-furo [3,2-c] pyrazole- 5-carboxylic (1)

image 1

The pyrrole-2-carboxylic acid (0.284 g, 0.00255 mol) was dissolved in dichloromethane (DCM, 30 ml). A few drops of anhydrous dimethylformamide (DMF) were added after the dropwise addition of oxalyl chloride (0.0153 g, 1.34 ml). After stirring overnight at room temperature, the solvent was removed in vacuo and the mixture was taken with toluene and evaporated to dryness (twice). This

25 was recently dissolved in dichloromethane (DCM, 25 ml) and a solution of (1-methyl-1-phenyl-ethyl) -amide of 3- (2-amino-benzoylamino) -1H-furo acid [3,2] -c] pyrazole 5-carboxylic acid (286 mg, 0.711 mmol), pyridine (4.27 mmol, 0.731 ml) and diisopropylethylamine (10.6 mmol, 0.858 ml) in dichloromethane (DCM, 30 ml) was added dropwise. The mixture was stirred at room temperature overnight. Subsequently, it was diluted

30 with dichloromethane, washed respectively with a saturated solution of sodium bicarbonate, with brine with water, and subsequently dried over sodium sulfate. The organic solvent was evaporated to dryness and the crude product was taken with toluene and evaporated to dryness. The crude product was subsequently dissolved in a 10% solution of triethylamine (TEA) in methanol and stirred at 50 ° C for two hours and at

5 room temperature overnight. The mixture was subsequently evaporated to dryness and the residue was purified by flash column chromatography on silica gel (eluting with dichloromethane-methanol 46/4). The isolated material was triturated with ethyl ether which produced 110 mg of the title compound.

[M + H] + 497;

10 1 H NMR (400 MHz, DMSO-D6) � ppm 1.69 (s, 6 H) 6.06 -6.21 (m, 1 H) 6.77 6.89 (m, 1 H) 6.94 -7.05 (m, 1 H) 7.15 -7.26 (m, 2 H) 7.27 -7.36 (m, J = 12.44 Hz, 3 H) 7.36 -7.46 (m, 2 H) 7.56-7.70 (m, 1 H) 8.08 (d, 1 H) 8.25 (s, 1 H) 8.63 (d, 1 H) 11.19 ( s, 1 H) 11.83 (s, 1 H) 11.89 -12.01 (m, 1 H) 12.65 (s, 1 H).

For the operation as previously reported and for starting from the appropriate intermediate 15, the following furo [3,2-c] pyrazole derivatives were prepared analogously.

(2) 3- {2 - [(Thiophene-2-carbonyl) -amino] benzoylamino} -1H-furo [3,2-c] pyrazole-5 (1-methyl-1-phenyl-ethyl) -amide -carboxylic. LC-MS: Rt 6.37; [M + H] + 514;

20 1 H NMR (400 MHz, DMSO-D6) � ppm 1.68 (s, 6 H) 7.13 (dd, 1 H) 7.20 (tt, 1 H) 7.25-7.34 (m, 3 H) 7.37 (s, 1 H) 7.38-7.44 (m, 2 H) 7.65 (ddd, 1 H) 7.78 (dd, 1 H) 7.84 (dd, 1 H) 8.09 (d, 1 H) 8.29 (s, 1 H) 8.53 (d, 1 H) 11.25 (s, 1 H) 11.91 -12.39 (m, 1 H ) 3- (2-Acetylamino-benzoylamino) -1H (1-methyl-1-phenyl-ethyl) -amide 12.64 (s, 1 H) 3H

Furo [3,2-c] pyrazol-5-carboxylic LC-MS: Rt 4.87; [M + H] + 446; 1 H NMR (400 MHz, DMSO-D6) � ppm 1.68 (s, 6 H) 2.09 (s, 3 H) 7.10-7.24 (m, J = 7.32 Hz, 2 H) 7.31 (d, J = 15.97 Hz, 3 H) 7.36-7.45 (m, 2 H) 7.54 (ddd, 1 H) 7.90 (d, 1 H) 8.23 -8.38 (m, 2 H) 10.80 (s, 1 H) 11.08 (s, 1 H) 12.56 (s, 1 H).

30 4) 3- (2-Acetylaminobenzoylamino) -1H-furo [3,2-c] pyrazol-5-carboxylic acid LEMS: 1- (1- (2-Fluoro-phenyl) -1-methyl-ethyl] -amide: Rt 4.93; [M + H] + 464; 1 H NMR (400 MHz, DMSO-D6) � ppm 1.75 (s, 6 H) 2.10 (s, 3 H) 7.03-7.32 (m,

5 H) 7.32 -7.44 (m, 2 H) 7.52 -7.60 (m, 1 H) 7.92 (d, 1 H) 8.32 (s, 1 H) 10.77 -10.94 35 (m, 1 H) 11.08 (s, 1 H) 12.57 (s, 1 H).

5) 3- {2 - [(1 H-Pyrrole-2-carbonyl) acid [1- (2-fluoro-phenyl) -1-methyl-ethyl] -amide)

amino] -benzoylamino} -1H-furo [3,2-c] pyrazol-5-carboxylic LC-MS: Rt 5.72; [M + H] + 515; 1 H NMR (400 MHz, DMSO-D6) � ppm 1.75 (s, 6 H) 6.08 -6.15 (m, 1 H) 6.80

5 6.85 (m, 1 H) 6.97 -7.01 (m, 1 H) 7.07 -7.24 (m, 3 H) 7.24 -7.32 (m, 1 H) 7 , 35 (s, 1 H) 7.41 (ddd, 1 H) 7.62 (ddd, 1 H) 8.07 (d, 1 H) 8.25 (s, 1 H) 8.64 (d, 1 H) 11.19 (s, 1 H) 11.78 -11.88 (m, 1 H) 11.90 -11.98 (m, 1 H) 12.64 (s, 1 H).

6) 3- (2-Isobutyrylamino-benzoylamino) -1Hfuro [3,2-c] pyrazol-5-carboxylic acid LC-MS: 1-methyl-1-phenyl-ethyl) -amide: Rt 5.75; [M + H] + 474;

1 H NMR (400 MHz, DMSO-D6) � ppm 1.14 (d, J = 6.83 Hz, 6 H) 1.68 (s, 6 H) 2.51 -2.63 (m, 1 H) 7.11 -7.24 (m, 2 H) 7.25 -7.35 (m, 3 H) 7.35 -7.44 (m, 2 H) 7.51 7.64 (m, 1 H ) 7.97 (d, J = 7.80 Hz, 1 H) 8.22 (s, 1 H) 8.42 (d, J = 8.29 Hz, 1 H) 11.09 (s, 2 H ) 12.58 (s, 1 H).

3- {2 - [(1-Methyl-1H-pyrrole-2-carbonyl) acid 1-methyl-1-phenyl-ethyl) -amide

amino] -benzoylamino} -1H-furo [3,2-c] pyrazol-5-carboxylic LC-MS: RT 6.32; [M + H] + 511; 1 H NMR (400 MHz, DMSO-D6) � ppm 1.68 (s, 6 H) 3.91 (s, 3 H) 6.05 (ddd, 1 H)

6.86 (ddd, 1 H) 7.04 (ddd, 1 H) 7.21 (s, 2 H) 7.27-7.33 (m, 2 H) 7.35 (s, 1 H) 7 , 38 20 7.46 (m, 2 H) 7.61 (ddd, 1 H) 8.06 (d, 1 H) 8.25 (s, 1 H) 8.60 (d, 1 H) 11, 17 (s, 1 H) 11.89 (s, 1 H) 12.64 (s, 1 H). 8) 3- {2 - [(2-Methyl-2H-pyrazol-3-carbonyl) amino] -benzoylamino} -1H-furo [3,2-c] 1-methyl-1-phenyl-ethyl) -amide ] pyrazol-5-carboxylic LC-MS: Rt 5.65; [M + H] + 512;

25 1 H NMR (400 MHz, DMSO-D6) � ppm 1.68 (s, 6 H) 4.11 (s, 3 H) 6.92 (d, 1 H) 7.15 -7.24 (m, 1 H) 7.26 -7.35 (m, 3 H) 7.36 (s, 1 H) 7.38 -7.47 (m, 3 H) 7.65 (ddd, 1 H) 8.08 (d, 1 H) 8.26 (s, 1 H) 8.51 (d, 1 H) 11.24 (s, 1 H) 12.03 (s, 1 H) 12.63 (s, 1 H ).

9) 3- {2 - [(1-Methyl-1H-pyrazol-3-carbonyl) amino] -benzoylamino} -1H-furo [3,2- (1-methyl-1-phenyl-ethyl) -amide c] pyrazole-5-carboxylic LC-MS: Rt 5.51; [M + H] + 512;

1 H NMR (400 MHz, DMSO-D6) � ppm 1.68 (s, 6 H) 3.87 (s, 3 H) 6.76 (d, 1 H) 7.14-7.45 (m, 7 H) 7.62 (ddd, 1 H) 7.82 (d, 1 H) 7.99 (d, 1 H) 8.36 (s, 1 H) 8.65 (d, 1 H) 11.06 (s, 1 H) 11.90 (s, 1 H) 12.63 (s, 1 H).

10) 3- (2-Benzoylamino-benzoylamino) -1H35 furo [3,2-c] pyrazol-5-carboxylic acid LC-MS (1-methyl-1-phenyl-ethyl) -amide: Rt 6.42; [M + H] + 508;

1 H NMR (400 MHz, DMSO-D6) � ppm 1.66 (s, 6 H) 7.16-7.24 (m, 1 H) 7.25 7.34 (m, 3 H) 7.35 - 7.45 (m, 4 H) 7.47 -7.61 (m, 2 H) 7.67 (dt, 1 H) 7.91 -8.00 (m, 2 H) 8.09 (d, 1 H) 8.29 (s, 1 H) 8.65 (d, 1 H) 11.22 (s, 1 H) 12.16 (s, 1 H) 12.64 (s, 1 H).

5-11) 3- {2 - [(5-Methyl-1H-pyrazol-3-carbonyl) acid 1-methyl-1-phenyl-ethyl) -amide)

amino] -benzoylamino} -1H-furo [3,2-c] pyrazol-5-carboxylic LC-MS: Rt 4.81; [M + H] + 512; 1 H NMR (400 MHz, DMSO-D6) � ppm 1.68 (s, 6 H) 2.27 (s, 3 H) 6.51 (s, 1 H)

7.15 -7.26 (m, 2 H) 7.26 -7.33 (m, 2 H) 7.36 -7.43 (m, 3 H) 7.61 (dt, 1 H) 7, 97 (d, 1 H) 10 8.33 (s, 1 H) 8.67 (d, 1 H) 11.07 (s, 1 H) 11.95 (s, 1 H) 12.62 (s, 1 H) 13.05 (s, 1 H). 12) 3- {2 - [(Thiazol-4-carbonyl) -amino] (1-methyl-1-phenyl-ethyl) -amide]

benzoylamino} -1H-furo [3,2-c] pyrazol-5-carboxylic LC-MS: Rt 5.86; [M + H] + 515; 1 H NMR (400 MHz, DMSO-D6) � ppm 1.68 (s, 6 H) 7.19 (tt, 1 H) 7.24-7.35 (m,

15 3 H) 7.34 -7.44 (m, 3 H) 7.65 (dt, 1 H) 8.00 (d, 1 H) 8.32 (s, 1 H) 8.54 (d, 1 H) 8.71 (d, 1 H) 9.21 (d, 1 H) 11.10 (s, 1 H) 12.29 (s, 1 H) 12.64 (s, 1 H). 13) 3- {4- (4-Methyl-piperazin-1-yl) -2 - [(1 H -pyrrol-2-carbonyl) -amino] -benzoylamino} (1-methyl-1-phenyl-ethyl) -amide} -1H-furo [3,2-c] pyrazol-5-carboxylic LC-MS: Rt 4.15; [M + H] + 595;

20 1 H NMR (400 MHz, DMSO-d6) � ppm 1.69 (s, 6 H) 2.26 (s, 3 H) 2.42 -2.61 (m, 4 H) 3.21 -3, 49 (m, 4 H) 6.10 (dd, 1 H) 6.67 -6.77 (m, 2 H) 6.82 (dd, 1 H) 7.00 (dd, 1 H) 7.35 -7.49 (m, 4 H) 7.52 -7.59 (m, 2 H) 8.02 (d, 1 H) 8.25 (br. S., 1 H) 8.39 (br. s., 1 H) 10.80 (s, 1 H) 11.72 (br. s., 1 H) 12.58 (s, 1 H).

14) 3- {4- (4-Methyl-piperazin-1-yl) -2 - [(1-methyl25 1H-pyrrole-2-carbonyl) - (1-methyl-1-phenyl-ethyl) -amide - amino] -benzoylamino} -1H-furo [3,2-c] pyrazol-5-carboxylic

LC-MS: Rt 4.54; [M + H] + 609; 1 H NMR (400 MHz, DMSO-d6) � ppm 1.68 (s, 6 H) 2.26 (s, 3 H) 2.46 -2.50 (m, 4 H) 3.33 -3.38 (m, 4 H) 3.92 (s, 3 H) 6.03 (dd, J = 3.84, 2.62 Hz, 1 H) 6.73 (dd, J = 9.08, 2.38 Hz, 1 H) 6.88 (dd, J = 4.02, 1.71 Hz, 1 H) 7.03 (t, J = 2.01 Hz, 1 H) 7.15 -7.23 (m , 1 HOUR)

30 7.25 -7.33 (m, 3 H) 7.37 -7.43 (m, 2 H) 8.02 (d, J = 9.15 Hz, 1 H) 8.25 (s, 1 H) 8.35 (d, J = 2.56 Hz, 1 H) 10.78 (s, 1 H) 12.56 (s, 1 H). 15) 3- {2 - [(1-Methyl-1H-imidazol-2-carbonyl) amino] -benzoylamino} -1H-furo [3,2- (1-methyl-1-phenyl-ethyl) -amide c] pyrazol-5-carboxylic LC-MS: Rt 6.08; [M + H] + 512; 35 1 H NMR (400 MHz, DMSO-d6) � ppm 1.67 (s, 6 H) 4.00 (s, 3 H) 7.03 (d, J = 0.61

Hz, 1 H) 7.17 (t, J = 7.19 Hz, 1 H) 7.35 (s, 1 H) 7.42 (br. S., 1 H) 7.61 (ddd, J = 7.90, 7.70, 1.00 Hz, 1 H) 7.97 (d, J = 7.68 Hz, 1 H) 8.28 (s, 1 H) 8.63 (d, J = 8 , 29 Hz, 1 H) 11.07 (s, 1 H) 12.15 (s, 1 H) 12.61 (s, 1 H). 16) 3- {2- [4- (4-Methyl-piperazin-1-yl) 5 benzoylamino] -benzoylamino} -1H-furo [3,2-1-methyl-1-phenyl-ethyl) -amide [3,2] -c] pyrazole-5-carboxylic [M + H] + 512; 1 H NMR (400 MHz, DMSO-d6) � ppm 1.68 (s, 6 H) 2.50 -3.77 (m, 11 H) 7.12 (d, 2 H) 7.16 -7.27 (m, 2 H) 7.27 -7.34 (m, 2 H) 7.37 -7.44 (m, 3 H) 7.59 -7.68 (m, 1 H) 7.85 (d , 2 H) 8.07 (dd, 1 H) 8.32 (br. S., 1 H) 8.69 (dd, 1 H) 11.24 (s, 1 H) 12.12 (s, 1 H) 12.65 (s, 1 H).

10

Claims (12)

 Claims 1. A compound of formula (I): image 1 in which 5 -A is an aryl or heteroaryl ring; wherein heteroaryl is an aromatic heterocyclic ring that may comprise a 5- or 6-membered heterocycle optionally benzocondensed with 1 to 3 heteroatoms selected from N, O or S; -NHZR5 is in ortho position to the CONH linker; 10 -R1 and R2 are the same or different and, independently of each other, represent a hydrogen atom, a linear or branched C1-C3 alkyl or a CONH2, -CH2OR 'or -CH2NR'R "or group, taken together with the carbon atom to which they are attached, R1 and R2 can form a C3-C6 alkyl cycle group; R 'and R "are the same or different and, in 15 independently of each other, represent a hydrogen atom or a linear or branched C1-C3 alkyl group or, taken together with the nitrogen atom to which they are attached, R ’and R" can form a heterocyclic ring of formula image 1 20 wherein R "’ is a hydrogen atom or a linear C1-C3 alkyl group or branched; -R3 is a hydrogen or halogen atom or a group selected from hydroxy, cyano, linear or branched C1-C3 alkyl, C1-C6 alkylamino and C1-C3 alkoxy; -R4 is a hydrogen or halogen atom or a group selected from hydroxy, Linear or branched C1-C3 alkyl, C1-C3 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, (1-methyl-piperazin-4 -yl), (morpholino-4-yl), (azetidin-1-yl) methyl, (pyrrolidin-1-yl) methyl, (piperidin-1-yl) methyl, (1-methyl-piperazin-4-yl) methyl, (morpholino-4-yl) methyl, (1-methyl-piperidin-4-yloxy) methyl, (C1C6 alkylamino) methyl and (C1-C6 dialkylamino) methyl; 10 -Z is a direct link,> C = O, or -C (= O) NH-; -R5 is hydrogen or an optionally substituted group selected from C1-C6 alkyl, C1-C6 alkenyl, C3-C6 cycloalkyl, aryl, heteroaryl and saturated heteroaryl; wherein heteroaryl is an aromatic heterocyclic ring that may comprise a 5- or 6-membered heterocycle optionally benzo-condensed with 1 to 3 15 heteroatoms selected from N, O or S or their pharmaceutically acceptable isomers, tautomers and salts. 2. A compound of formula (I) as defined in claim 1 wherein R1 and R2 are not hydrogen atoms. 3. A compound of formula (I) as defined in claim 1 or 2 Wherein A is an optionally substituted thienyl, furyl, pyrrolyl or phenyl group. 4. A compound of formula (I) as defined in claim 1 or 2 wherein A is a phenyl group and R4 is in position 4 and represents a hydrogen, halogen, methoxy, azetidin-1-yl, pyrrolidine group -1-yl, piperidin-1-yl, (1-methyl Piperazin-4-yl), (morpholino-4-yl), (azetidin-1-yl) methyl, (pyrrolidin-1-yl) methyl, (piperidin-1-yl) methyl, (1-methyl-piperazin-4- il) methyl, (morpholino-4-yl) methyl, (1-methyl-piperidin-4-yloxy) methyl, (C1-C6 alkylamino) methyl or (C1-C6 dialkylamino) methyl. 5. A compound of formula (I) as defined in any one of the preceding claims wherein Z is> C = O. 6. A compound of formula (I) as defined in any one of the preceding claims wherein R1 and R2 are both a methyl group or, taken together with the carbon atom to which they are attached, form a C3C6 cycloalkyl group .

7.

A compound of formula (I) as defined in any one of the preceding claims wherein R3 represents a hydrogen atom or

halogen

8.

A compound selected from the group consisting of: 3- {2 - [(1 H -pyrrol-2-carbonyl) -amino] benzoylamino} -1H-furo [3-methyl-1-phenyl-ethyl) -amide , 2-c] pyrazol-5-carboxylic; 3- {2 - [(Thiophene-2-carbonyl) -amino] benzoylamino} -1H-furo [3,2-c] pyrazole-5-carboxylic acid 5 (1-methyl-1-phenyl-ethyl) -amide ; 3- {2 - [(1H-Pyrrol-2-carbonyl) -amino] benzoylamino} -1H-furo [3,2-c] [1- (2-Fluoro-phenyl) -methyl-ethyl] -amide pyrazole-5-carboxylic; 3- {2 - [(1-Methyl-1H-pyrrol-2-carbonyl) -amino] 10-benzoylamino} -1H-furo [3,2-c (1-methyl-1-phenyl-ethyl) -amide ] pyrazole-5-carboxylic; 3- {2 - [(2-Methyl-2H-pyrazol-3-carbonyl) -amino] benzoylamino} -1H-furo [3,2-c] pyrazole-1-methyl-1-phenyl-ethyl) -amide -5-carboxylic; 3- {2 - [(1-Methyl-1 H -pyrazol-3-carbonyl) -amino] benzoylamino} -1H-furo [3,2-c] (1-methyl-1-phenyl-ethyl) -amide pyrazole-5-carboxylic; 3- (2-Benzoylamino-benzoylamino) -1Huro [3,2-c] pyrazol-5-carboxylic acid (1-methyl-1-phenyl-ethyl) -amide; 3- {2 - [(5-methyl-1 H -pyrazol-3-carbonyl) -amino] benzoylamino} -1H-furo [3,2-c] (1-methyl-1-phenyl-ethyl) -amide pyrazole-5-carboxylic; 3- {2 - [(Thiazol-4-carbonyl) -amino] 20 benzoylamino} -1H-furo [3,2-c] pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl) -amide ; 3- {4- (4-Methyl-piperazin-1-yl) -2 - [(1 H -pyrrole-2-carbonyl) -amino] -benzoylamino} -1H (1-methyl-1-phenyl-ethyl) -amide -furo [3,2-c] pyrazol-5-carboxylic; 3- {4- (4-Methyl-piperazin-1-yl) -2 - [(1-methyl-1H-pyrrol-2-carbonyl) -amino] - (1-methyl-1-phenyl-ethyl) -amide] - benzoylamino} -1H-furo [3,2-c] pyrazol-5-carboxylic acid and

3- {2 - [(1-Methyl-1 H -imidazol-2-carbonyl) amino] -benzoylamino} -1H-furo [3,2-c (1-methyl-1-phenyl-ethyl) -amide ] pyrazole-5-carboxylic; or its pharmaceutically acceptable isomers, tautomers and salts. 9. A process for preparing the compounds of formula (I) and pharmaceutically acceptable salts thereof as defined in claim 1, such The process comprises: a) reaction of a bicyclic compound of formula (II): image 1 wherein ALK is a C1-C4 alkyl group with any suitable protective agent of the nitrogen atom of pyrazole; b) acylation of the resulting compound of formula (III): image 1 wherein ALK is as defined above and Q represents any suitable protective agent of pyrazole nitrogen, with a compound of formula (IV): image 1 Wherein A and R4 are as defined in claim 1 and LG represents a suitable leaving group; c) hydrolysis of the alkyl ester group and removal of the protective group Q of the resulting compound of formula (V): image 1 fifteen in which ALK, A, R4 and Q are as defined above; d) reaction of the resulting compound of formula (VI): image 1 wherein A and R4 are as defined above, with a compound of formula (VII) image 1 wherein R1, R2 and R3 are as defined in claim 1, in the presence of any suitable condensing agent; e) reduce the nitro group of the resulting compound of formula (VIII) image 1 10 wherein A, R1, R2, R3, R4 and Q are as defined above; f) acylation of the resulting compound of formula (IX): image 1 wherein A, R1, R2, R3 and R4 are as defined above, with a compound of formula (X) or (XI): R5-Z-LG (X) 5 R5-NCO (XI) wherein Z is> C = O or -C (= O) NH-, R5 is as defined in claim 1 and LG is as defined above; 10 g) selective deacylation of the resulting compound of formula (XII): image 1 wherein A, R1, R2, R3, R4 and Q are as defined above and Z is> C = O or -C (= O) NH-, by the selective hydrolysis of the ZR5 substituent of the pyrazolic nitrogen to obtain a compound of formula (I) in which A, R1, R2, R3 and R4 are 15 as defined above and Z is> C = O or -C (= O) NH-, or f) treat a compound of formula (IX) as defined above with a carbonyl compound of formula W-CO-Y (XIII) in which W and Y are hydrogen atoms or an optionally substituted group selected from C1-C5 alkyl, C1-C5 cycloalkyl, aryl, heteroaryl or saturated heteroaryl, in the presence of a suitable reducing agent, to obtain a compound of formula (I) in which A, R1, R2, R3 and R4 are as defined above and Z is a direct bond and, if desired or if necessary, h) convert a compound of formula (I) as defined above into a Compound of formula (I) different by known reactions, or converting a compound of formula (I) as defined above into a pharmaceutically acceptable salt or converting the salt thereof into the compound of formula (I) free as defined above. 10. A process for preparing a compound of the formula (I) as defined in claim 1, comprising: i) reducing the nitro group of the compound of formula (V) as defined in the claim 9, and j) acylate the resulting compound of formula (XIV): image 1 wherein A, R4, ALK and Q are as defined in claim 9, with a compound of formula (X) or (XI) as defined in claim 9 to obtain a compound of formula (XV): image 1 wherein A, R4, R5, ALK and Q are as defined in claim 9 and Z is> C = O or -C (= O) NH-; or j ’) treat a compound of formula (XIV) as defined above with a Carbonyl compound of formula W-CO-Y (XIII) as described in claim 9, to obtain a compound of formula (XV) wherein A, R4, R5, ALK and Q are as defined above and Z is a direct link; k) hydrolyze the alkyl ester group and remove the protecting group Q of the resulting compound formula (XV) in which Z is> C = O or -C (= O) NH- or a direct bond; l) reacting the resulting compound of formula (XVI) image 1 wherein A, R4, R5 and Z are as defined above, with a compound of formula (VII) as described in claim 9; m) converting a compound of formula (I) as defined above into a compound of formula (I) different by known reactions or converting a compound of formula (I) as defined above into a pharmaceutically acceptable salt or convert the salt thereof into the compound of free formula (I) (I) as defined above. 11. A pharmaceutical composition comprising an amount Therapeutically effective of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, and at least one pharmaceutically acceptable excipient, carrier and / or diluent. 12. A pharmaceutical composition according to claim 11 further comprising one or more chemotherapeutic agents. 13. A product or kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, or pharmaceutical compositions thereof as defined in claim 11 and one or more chemotherapeutic agents. , in the form of a combined preparation for simultaneous, separate or sequential use in anticancer therapy. 14. A compound of formula (I) or a pharmaceutically acceptable salt, as defined in claim 1, for use as a medicament. 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 14 for use as a medicament for treating a disease caused and / or associated with deregulated IGF-1R or Aurora activity. 25 kinases